Electron tunneling reactions are critical in photosynthesis, oxidative phosphorylation, drug metabolism, biosynthesis, and catalysis. The success or failure or metabolic pathways depends upon the rates of these reactions, which in turn, are controlled by the structure of the medium between electron donor and acceptor. The means by which proteins, nucleic acids, and protein-protein complexes control these reaction rates will be the subject of our investigations (competitive renewal of Grant R01- GM48043). The influence of protein primary, secondary, tertiary, and quaternary structure, protein/protein docking interactions, and protein dynamics on electron transport rates will be probed using new quantitatively reliable methods in the photosynthetic reaction center/cytochrome c/2 complex, cytochrome c peroxidase/cytochrome c complex, cytochrome b/562 and cytochrome c. In addition, new reduced but exact methods of representing the results of protein electron transfer calculations will produce interpretative tools as simple and intuitive as Pathways analysis, but quantitatively reliable. The ubiquitous nature of electron transfer processes in biosynthesis and energy transduction makes them a natural target for investigation. These investigations involve quantum mechanical tunneling of an electron, and tunneling processes display an exquisite sensitivity to the structure of the barrier being traversed. Therefore, if quantitatively understood, these electron tunneling reactions could be used as diagnostics of macromolecule structure (secondary structure in proteins, DNA lesions, etc.) and could be manipulated in a medical setting to control drug metabolism (by cytochrome P/450) or DNA biosynthesis (by ribonucleotide reductase). This research project will be carried out collaboratively between the University of Pittsburgh Department of Chemistry and the University of California, San Diego Department of Physics. This proposal is intended to allow the continuation of collaborative studies that led to the Pathway model of protein electron transfer reactions, related multi- pathway methods, and their numerical implementations.